tbuckley/cabot-search huggingface dataset:
Gonadotropin-Releasing Hormone and Its Analogues
Authors: Jane F. Desforges, P. Michael Conn, William F. Crowley
Journal: New England Journal of Medicine (1991)

RESEARCH into the neuroendocrine control of reproduction by gonadotropin-releasing hormone (GnRH) has witnessed a remarkable two decades. From the isolation and chemical characterization of GnRH in 1971 through the awarding of the Nobel Prize to Drs. Serially and Guillemin for these accomplishments shortly thereafter, the translation from basic discovery to clinical usefulness has been swift. Food and Drug Administration approvals of GnRH-agonist analogues for the treatment of prostate cancer, endometriosis, and precocious puberty, as well as the use of natural GnRH to induce ovulation, are examples of the clinical usefulness of these fundamental observations. Numerous clinical therapies designed to stimulate . . .
A Bovine Albumin Peptide as a Possible Trigger of Insulin-Dependent Diabetes Mellitus
Authors: Jukka Karjalainen, Julio M. Martin, Mikael Knip, Jorma Ilonen, Brian H. Robinson, Erkki Savilahti, Hans K. Akerblom, Hans-Michael Dosch
Journal: New England Journal of Medicine (1992)

Cow's milk has been implicated as a possible trigger of the autoimmune response that destroys pancreatic beta cells in genetically susceptible hosts, thus causing diabetes mellitus. Studies in animals have suggested that bovine serum albumin (BSA) is the milk protein responsible, and an albumin peptide containing 17 amino acids (ABBOS) may be the reactive epitope. Antibodies to this peptide react with p69, a beta-cell surface protein that may represent the target antigen for milk-induced beta-cell—specific immunity.
Reduction in 1,25-Dihydroxyvitamin D in Children with Increased Lead Absorption
Authors: John F. Rosen, Russell W. Chesney, Alan Hamstra, Hector F. DeLuca, Kathryn R. Mahaffey
Journal: New England Journal of Medicine (1980)

STUDIES in laboratory animals have demonstrated that a diet low in calcium increases lead retention and that there are associated biochemical and morphologic manifestations of enhanced lead toxicity.1,2 This increased toxicity has been attributed to an increase in the gastrointestinal absorption of lead, although the precise roles of dietary calcium and vitamin D in modifying lead absorption have not been defined. Recent experimental observations suggest that calcium and lead compete for similar binding sites on mucosal proteins in the intestine.3 Nonetheless, lead is bound mainly to a high-molecular-weight mucosal protein, whereas calcium is bound primarily to a lower-molecular-weight protein . . .
Adjuvant Endocrine Therapy for Women With Hormone Receptor–Positive Breast Cancer: ASCO Clinical Practice Guideline Focused Update
Authors: Harold J. Burstein, Christina Lacchetti, Holly Anderson, Thomas A. Buchholz, Nancy E. Davidson, Karen A. Gelmon, Sharon H. Giordano, Clifford A. Hudis, Alexander J. Solky, Vered Stearns, Eric P. Winer, Jennifer J. Griggs
Journal: Journal of Clinical Oncology (2018)

Purpose To update the ASCO clinical practice guideline on adjuvant endocrine therapy based on emerging data about the optimal duration of aromatase inhibitor (AI) treatment. Methods ASCO conducted a systematic review of randomized clinical trials from 2012 to 2018. Guideline recommendations were based on the Panel’s review of the evidence from six trials. Results The six included studies of AI treatment beyond 5 years of therapy demonstrated that extension of AI treatment was not associated with an overall survival advantage but was significantly associated with lower risks of breast cancer recurrence and contralateral breast cancer compared with placebo. Bone-related toxic effects were more common with extended AI treatment. Recommendations The Panel recommends that women with node-positive breast cancer receive extended therapy, including an AI, for up to a total of 10 years of adjuvant endocrine treatment. Many women with node-negative breast cancer should consider extended therapy for up to a total of 10 years of adjuvant endocrine treatment based on considerations of recurrence risk using established prognostic factors. The Panel noted that the benefits in absolute risk of reduction were modest and that, for lower-risk node-negative or limited node-positive cancers, an individualized approach to treatment duration that is based on considerations of risk reduction and tolerability was appropriate. A substantial portion of the benefit for extended adjuvant AI therapy was derived from prevention of second breast cancers. Shared decision making between clinicians and patients is appropriate for decisions about extended adjuvant endocrine treatment, including discussions about the absolute benefits in the reduction of breast cancer recurrence, the prevention of second breast cancers, and the impact of adverse effects of treatment. Additional information can be found at www.asco.org/breast-cancer-guidelines .
Intracellular calcium handling in isolated ventricular myocytes from patients with terminal heart failure.
Authors: D J Beuckelmann, M Näbauer, E Erdmann
Journal: Circulation (1992)

BACKGROUND Experiments were performed in human ventricular myocytes to investigate properties of excitation-contraction coupling in patients with terminal heart failure. Myocytes were isolated from left ventricular myocardium of patients with cardiac failure caused by dilated or ischemic cardiomyopathy undergoing transplantation. These results were compared with those obtained from cells of healthy donor hearts that for technical reasons were not suitable for transplantation. METHODS AND RESULTS [Ca2+]i transients and Ca2+ currents were recorded from isolated cells under voltage clamp perfused internally with the Ca2+ indicator fura 2. In cells that were stimulated externally, the cell-permeant form of the indicator, fura 2-AM, was used. When action potentials were to be recorded, cells were stimulated in current clamp mode. Unstimulated Ca2+ current densities were not significantly different in myopathic and control cells. In diseased myocytes, resting [Ca2+]i levels were 165 +/- 61 nmol/l, compared with 95 +/- 47 nmol/l in normal cells. With 5 mmol/l Na+ in the pipette, peak [Ca2+]i transients were 367 +/- 109 and 746 +/- 249 nmol/l, respectively. The decline of [Ca2+]i during diastole was significantly slower in myopathic cells than in control cells. This was a result of a prolongation of the action potential and of a reduced Ca2+ sequestration by the sarcoplasmic reticulum. CONCLUSIONS These results may partly explain the alterations of contractility in vivo in patients with heart failure.
Decreased NKX3.1 Protein Expression in Focal Prostatic Atrophy, Prostatic Intraepithelial Neoplasia, and Adenocarcinoma: Association with Gleason Score and Chromosome 8p Deletion
Authors: Carlise R. Bethel, Dennis Faith, Xiang Li, Bin Guan, Jessica L. Hicks, Fusheng Lan, Robert B. Jenkins, Charles J. Bieberich, Angelo M. De Marzo
Journal: Cancer Research (2006)

Abstract NKX3.1 is a homeobox gene located at chromosome 8p21.2, and one copy is frequently deleted in prostate carcinoma. Prior studies of NKX3.1 mRNA and protein in human prostate cancer and prostatic intraepithelial neoplasia (PIN) have been conflicting, and expression in focal prostate atrophy lesions has not been investigated. Immunohistochemical staining for NKX3.1 on human tissue microarrays was decreased in most focal atrophy and PIN lesions. In carcinoma, staining was inversely correlated with Gleason grade. Fluorescence in situ hybridization showed that no cases of atrophy had loss or gain of 8p, 8 centromere, or 8q24 (C-MYC) and only 12% of high-grade PIN lesions harbored loss of 8p. By contrast, NKX3.1 staining in carcinoma was correlated with 8p loss and allelic loss was inversely related to Gleason pattern. Quantitative reverse transcription-PCR for NKX3.1 mRNA using microdissected atrophy revealed a concordance with protein in five of seven cases. In carcinoma, mRNA levels were decreased in 6 of 12 cases but mRNA levels correlated with protein levels in only 4 of 12 cases, indicating translational or post-translational control. In summary, NKX3.1 protein is reduced in focal atrophy and PIN but is not related to 8p allelic loss in these lesions. Therefore, whereas genetic disruption of NKX3.1 in mice leads to PIN, nongenetic mechanisms reduce NKX3.1 protein levels early in human prostate carcinogenesis, which may facilitate both proliferation and DNA damage in atrophic and PIN cells. Monoallelic deletions on chromosome 8p are associated with more advanced invasive and aggressive disease. (Cancer Res 2006; 66(22): 10683-90)
RASSF1A Interacts with Microtubule-Associated Proteins and Modulates Microtubule Dynamics
Authors: Ashraf Dallol, Angelo Agathanggelou, Sarah L. Fenton, Jalal Ahmed-Choudhury, Luke Hesson, Michele D. Vos, Geoffrey J. Clark, Julian Downward, Eamonn R. Maher, Farida Latif
Journal: Cancer Research (2004)

Abstract The candidate tumor suppressor gene RASSF1A is inactivated in many types of adult and childhood cancers. However, the mechanisms by which RASSF1A exerts its tumor suppressive functions have yet to be elucidated. To this end, we performed a yeast two-hybrid screen to identify novel RASSF1A-interacting proteins in a human brain cDNA library. Seventy percent of interacting clones had homology to microtubule-associated proteins, including MAP1B and VCY2IP1/C19ORF5. RASSF1A association with MAP1B and VCY2IP1/C19ORF5 was subsequently confirmed in mammalian cell lines. This suggested that RASSF1A may exert its tumor-suppressive functions through interaction with the microtubules. We demonstrate that RASSF1A associates with the microtubules, causing them to exist as hyperstabilized circular bundles. We found that two naturally occurring tumor-associated missense substitutions in the RASSF1A coding region, C65R and R257Q, perturb the association of RASSF1A with the microtubules. The C65R and R257Q in addition to VCY2IP1/C19ORF5 showed reduced ability to induce microtubule acetylation and were unable to protect the microtubules against the depolymerizing action of nocodazole. In addition, wild-type RASSF1A but not the C65R or the R257Q is able to block DNA synthesis. Our data identify a role for RASSF1A in the regulation of microtubules and cell cycle dynamics that could be part of the mechanism(s) by which RASSF1A exerts its growth inhibition on cancer cells.
Angina Pectoris and the Placebo Effect
Authors: Howard L. Bleich, Mary Jean Moore, Herbert Benson, David P. McCallie
Journal: New England Journal of Medicine (1979)

THE placebo effect is a component of any therapeutic intervention, and its influence is seen in many diseases.1 2 3 4 5 The symptoms of angina pectoris, in particular, are responsive to the placebo effect. Many of the treatments used since Heberden's6 description of this disease in 1772 are now known to have no specific physiologic effect. Since the diagnostic criteria for angina pectoris and the evaluation of its severity have not changed appreciably in 200 years, a review of the reported effectiveness of some of these inactive, abandoned treatments affords a historical perspective on the contribution of the placebo effect and permits quantification . . .
A Prospective Trial of 68Ga-PSMA and 18F-FDG PET/CT in Nonmetastatic Prostate Cancer Patients with an Early PSA Progression During Castration
Authors: Beihe Wang, Chang Liu, Yu Wei, Jin Meng, Yingjian Zhang, Hualei Gan, Xiaoping Xu, Fangning Wan, Jian Pan, Xuejun Ma, Silong Hu, Stephen J. Freedland, Shaoli Song, DingWei Ye, Yao Zhu
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Tumor heterogeneity and burden, which impact treatment outcome in prostate cancer, are rarely evaluated using next-generation imaging. Experimental Design: The trial prospectively included 37 patients who had an early PSA progression (≤2 ng/mL) during castration and high-risk (PSA doubling time ≤10 months) nonmetastatic disease by conventional imaging. All patients underwent both 68Ga-PSMA and 18F-FDG PET/CT. Lesions were classified into PSMA+FDG± lesions and PSMA-FDG+ lesions. The primary endpoint was the prevalence of PSMA-FDG+ disease. Tumor burden, predictors for positive imaging, and suitability for oligometastases-directed therapy (OMDT) were also evaluated. Results: All patients were treated with RP and the median duration of castration was 23 months. The median PSA at imaging was 0.57 ng/mL. Overall, 114 lesions were detected in 29 of the 37 patients. A high prevalence (73%) of N+/M+ disease was observed. Of the 114 lesions, 81 were PSMA+FDG± and 33 were PSMA-FDG+. Per patient level, 9 men (24%; 95% confidence interval: 10%–39%) showed at least one new PSMA-FDG+ lesions. A short PSA doubling time (P = 0.009, OR = 8.000) was associated with PSMA+FDG± disease, while a high Gleason grade group (P = 0.022, OR = 13.091) with PSMA-FDG+ disease. Nineteen patients (51%) with 51 lesions, including 10 PSMA-FDG+ lesions, could be enrolled for OMDT. Among different disease stages, PSMA-FDG+ disease was rarely detected in the hormone-sensitive cohort, but frequently found in the castration-resistant cohort. Conclusions: Using 68Ga-PSMA and 18F-FDG PET, we observed a high prevalence of N+/M+ disease and a significant proportion of PSMA-FDG+ disease in patients with an early PSA progression during castration (ChiCTR1900022634).
Carbonic anhydrase inhibitors
Authors: Claudiu T. Supuran, Andrea Scozzafava, Angela Casini
Journal: Medicinal Research Reviews (2002)

Abstract At least 14 different carbonic anhydrase (CA, EC 4.2.1.1) isoforms were isolated in higher vertebrates, where these zinc enzymes play crucial physiological roles. Some of these isozymes are cytosolic (CA I, CA II, CA III, CA VII), others are membrane‐bound (CA IV, CA IX, CA XII, and CA XIV), CA V is mitochondrial and CA VI is secreted in saliva. Three acatalytic forms are also known, which are denominated CA related proteins (CARP), CARP VIII, CARP X, and CARP XI. Several important physiological and physio‐pathological functions are played by many CA isozymes, which are strongly inhibited by aromatic and heterocyclic sulfonamides as well as inorganic, metal complexing anions. The catalytic and inhibition mechanisms of these enzymes are understood in detail, and this helped the design of potent inhibitors, some of which possess important clinical applications. The use of such enzyme inhibitors as antiglaucoma drugs will be discussed in detail, together with the recent developments that led to isozyme‐specific and organ‐selective inhibitors. A recent discovery is connected with the involvement of CAs and their sulfonamide inhibitors in cancer: several potent sulfonamide inhibitors inhibited the growth of a multitude of tumor cells in vitro and in vivo , thus constituting interesting leads for developing novel antitumor therapies. Furthermore, some other classes of compounds that interact with CAs have recently been discovered, some of which possess modified sulfonamide or hydroxamate moieties. Some sulfonamides have also applications as diagnostic tools, in PET and MRI or as antiepileptics or for the treatment of other neurological disorders. Future prospects for drug design applications for inhibitors of these ubiquitous enzymes are also discussed. © 2002 Wiley Periodicals, Inc. Med Res Rev, 23, No. 2, 146–189, 2003
Efficacy and Safety of Dapagliflozin in the Elderly: Analysis From the DECLARE–TIMI 58 Study
Authors: Avivit Cahn, Ofri Mosenzon, Stephen D. Wiviott, Aliza Rozenberg, Ilan Yanuv, Erica L. Goodrich, Sabina A. Murphy, Deepak L. Bhatt, Lawrence A. Leiter, Darren K. McGuire, John P.H. Wilding, Ingrid A.M. Gause-Nilsson, Martin Fredriksson, Peter A. Johansson, Anna Maria Langkilde, Marc S. Sabatine, Itamar Raz
Journal: Diabetes Care (2019)

OBJECTIVE Data regarding the effects of sodium–glucose cotransporter 2 inhibitors in the elderly (age ≥65 years) and very elderly (age ≥75 years) are limited. RESEARCH DESIGN AND METHODS The Dapagliflozin Effect on Cardiovascular Events (DECLARE)–TIMI 58 assessed cardiac and renal outcomes of dapagliflozin versus placebo in patients with type 2 diabetes. Efficacy and safety outcomes were studied within age subgroups for treatment effect and age-based treatment interaction. RESULTS Of the 17,160 patients, 9,253 were &amp;lt;65 years of age, 6,811 ≥65 to &amp;lt;75 years, and 1,096 ≥75 years. Dapagliflozin reduced the composite of cardiovascular death or hospitalization for heart failure consistently, with a hazard ratio (HR) of 0.88 (95% CI 0.72, 1.07), 0.77 (0.63, 0.94), and 0.94 (0.65, 1.36) in age-groups &amp;lt;65, ≥65 to &amp;lt;75, and ≥75 years, respectively (interaction P value 0.5277). Overall, dapagliflozin did not significantly decrease the rates of major adverse cardiovascular events, with HR 0.93 (95% CI 0.81, 1.08), 0.97 (0.83, 1.13), and 0.84 (0.61, 1.15) in age-groups &amp;lt;65, ≥65 to &amp;lt;75, and ≥75 years, respectively (interaction P value 0.7352). The relative risk reduction for the secondary prespecified cardiorenal composite outcome ranged from 18% to 28% in the different age-groups with no heterogeneity. Major hypoglycemia was less frequent with dapagliflozin versus placebo, with HR 0.97 (95% CI 0.58, 1.64), 0.50 (0.29, 0.84), and 0.68 (0.29, 1.57) in age-groups &amp;lt;65, ≥65 to &amp;lt;75, and ≥75 years, respectively (interaction P value 0.2107). Safety outcomes, including fractures, volume depletion, cancer, urinary tract infections, and amputations were balanced with dapagliflozin versus placebo, and acute kidney injury was reduced, all regardless of age. Genital infections that were serious or led to discontinuation of the study drug and diabetic ketoacidosis were uncommon, yet more frequent with dapagliflozin versus placebo, without heterogeneity (interaction P values 0.1058 and 0.8433, respectively). CONCLUSIONS The overall efficacy and safety of dapagliflozin are consistent regardless of age.
A Potential Decline in Life Expectancy in the United States in the 21st Century
Authors: S. Jay Olshansky, Douglas J. Passaro, Ronald C. Hershow, Jennifer Layden, Bruce A. Carnes, Jacob Brody, Leonard Hayflick, Robert N. Butler, David B. Allison, David S. Ludwig
Journal: New England Journal of Medicine (2005)

Forecasts of life expectancy are an important component of public policy that influence age-based entitlement programs such as Social Security and Medicare. Although the Social Security Administration recently raised its estimates of how long Americans are going to live in the 21st century, current trends in obesity in the United States suggest that these estimates may not be accurate. From our analysis of the effect of obesity on longevity, we conclude that the steady rise in life expectancy during the past two centuries may soon come to an end.
Abstract 13491: Spermidine Improves Angiogenic Capacity in Senescent Endothelial Cells and Enhances Ischemia Induced Neovascularization in Aged Mice
Authors: Daisuke Ueno, Koji Ikeda, Ekura Yamazaki, Akiko Katayama, Satoaki Matoba
Journal: Circulation (2022)

Aging is closely associated with high morbidity and mortality of various diseasesincluding cardiovascular disease. Cellular senescence has been cruciallyinvolved in the mechanisms underlying age-related diseases, and vascularendothelial cells &lt;ECs&gt; become senescent during aging. Spermidine, a naturallyoccurring polyamine, is an emerging organic compound that shows various anti-aging effects. Serum spermidine concentration decreases during aging inhuman, and dietary spermidine has been reported to extend healthy lifespanand delay the age-related decline in cognitive and physical performance inmany species such as yeast, worms, flies, and mice. Here, we explored aneffect of spermidine on age-associated decline in angiogenesis. Replicativesenescent ECs were prepared by culturing human ECs for an extended perioduntil passage 18-20, and cellular senescence was confirmed by loss ofproliferation capacity, increased CDK inhibitors expression, and senescence-associated beta-Gal activity. Intracellular polyamine contents were significantlyreduced in replicative senescent ECs, which was recovered by spermidinesupplementation. Spermidine supplementation improved the declinedangiogenic capacities including tube-formation on Matrigel in senescent ECs,while senescence features such as reduced proliferation and senescence-associated beta-Gal activity were not affected. Mechanistically, spermidinesupplementation accelerated the static autophagy flux, and improvedmitochondrial quality, e.g. reduced mitochondrial ROS and preservedmitochondrial membrane potential, in senescent ECs. Ischemia-inducedneovascularization was assessed using the hind-limb ischemia model in youngand aged mice. Blood flow recovery and neovascularization in ischemic musclewere considerably impaired in aged mice comparing to those in young mice. Ofnote, dietary spermidine significantly enhanced ischemia-induced angiogenesis,and improved the blood flow recovery in the ischemic limb, especially in agedmice. Our results reveal new mechanistic insights in anti-aging property ofspermidine, and suggest its therapeutic potential against ischemiccardiovascular disease, particularly in elderly population.
Chronic Obstructive Pulmonary Disease (Japanese Version)
Authors: Wassim W. Labaki, Sharon R. Rosenberg
Journal: Annals of Internal Medicine (2020)

In the Clinic4 August 2020Chronic Obstructive Pulmonary Disease (Japanese Version)Wassim W. Labaki, MD, MS and Sharon R. Rosenberg, MD, MSWassim W. Labaki, MD, MSUniversity of Michigan, Ann Arbor, Michigan (W.W.L.) and Sharon R. Rosenberg, MD, MSNorthwestern University, Chicago, Illinois (S.R.R.)Author, Article, and Disclosure Informationhttps://doi.org/10.7326/IsTranslatedFrom_AITC202008040_Japanese SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Editors' Note: This article (available in PDF format) is the translated Japanese version of In the Clinic: Chronic Obstructive Pulmonary Disease (Labaki WW, Rosenberg SR. Chronic Obstructive Pulmonary Disease. Ann Intern Med. 2020;173:ITC17-ITC32. doi:10.7326/AITC202008040. Author, Article, and Disclosure InformationAuthors: Wassim W. Labaki, MD, MS; Sharon R. Rosenberg, MD, MSAffiliations: University of Michigan, Ann Arbor, Michigan (W.W.L.)Northwestern University, Chicago, Illinois (S.R.R.)Funding Source: American College of Physicians.Acknowledgment: The authors thank Michael R. Littner, MD, author of the previous version of this In the Clinic.Disclosures: Dr. Labaki, ACP Contributing Author, reports nonfinancial support from Pulmonx and personal fees from Konica Minolta outside the submitted work. Dr. Rosenberg, ACP Contributing Author, has nothing to disclose. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M20-0505.With the assistance of additional physician writers, the editors of Annals of Internal Medicine develop In the Clinic using MKSAP and other resources of the American College of Physicians. The patient information page was written by Monica Lizarraga from the Patient and Interprofessional Partnership Initiative at the American College of Physicians.In the Clinic does not necessarily represent official ACP clinical policy. For ACP clinical guidelines, please go to https://www.acponline.org/clinical_information/guidelines/. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoChronic Obstructive Pulmonary Disease Wassim W. Labaki and Sharon R. Rosenberg Metrics 4 August 2020Volume 173, Issue 3Page: JITC17-JITC32KeywordsBronchodilatorsChronic obstructive pulmonary diseaseDyspneaEmphysemaExerciseForced expiratory volume in the first second of expirationLungsMortalityOxygenThorax ePublished: 16 May 2023 Issue Published: 4 August 2020 Copyright & PermissionsCopyright © 2020 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...